A conserved protein inhibitor brings under check the activity of RNase E in cyanobacteria.

The bacterial ribonuclease RNase E plays a key role in RNA metabolism. Yet, with a large substrate spectrum and poor substrate specificity, its activity must be well controlled under different conditions. Only a few regulators of RNase E are known, limiting our understanding on posttranscriptional regulatory mechanisms in bacteria. Here we show that, RebA, a protein universally present in cyanobacteria, interacts with RNase E in the cyanobacterium Anabaena PCC 7120. Distinct from those known regulators of RNase E, RebA interacts with the catalytic region of RNase E, and suppresses the cleavage activities of RNase E for all tested substrates. Consistent with the inhibitory function of RebA on RNase E, depletion of RNase E and overproduction of RebA caused formation of elongated cells, whereas the absence of RebA and overproduction of RNase E resulted in a shorter-cell phenotype. We further showed that the morphological changes caused by altered levels of RNase E or RebA are dependent on their physical interaction. The action of RebA represents a new mechanism, potentially conserved in cyanobacteria, for RNase E regulation. Our findings provide insights into the regulation and the function of RNase E, and demonstrate the importance of balanced RNA metabolism in bacteria.

Cyclic di-GMP inhibits nitrate assimilation by impairing the antitermination function of NasT in Pseudomonas putida.

The ubiquitous bacterial second messenger cyclic diguanylate (c-di-GMP) coordinates diverse cellular processes through its downstream receptors. However, whether c-di-GMP participates in regulating nitrate assimilation is unclear. Here, we found that NasT, an antiterminator involved in nitrate assimilation in Pseudomonas putida, specifically bound c-di-GMP. NasT was essential for expressing the nirBD operon encoding nitrite reductase during nitrate assimilation. High-level c-di-GMP inhibited the binding of NasT to the leading RNA of nirBD operon (NalA), thus attenuating the antitermination function of NasT, resulting in decreased nirBD expression and nitrite reductase activity, which in turn led to increased nitrite accumulation in cells and its export. Molecular docking and point mutation assays revealed five residues in NasT (R70, Q72, D123, K127 and R140) involved in c-di-GMP-binding, of which R140 was essential for both c-di-GMP-binding and NalA-binding. Three diguanylate cyclases (c-di-GMP synthetases) were found to interact with NasT and inhibited nirBD expression, including WspR, PP_2557, and PP_4405. Besides, the c-di-GMP-binding ability of NasT was conserved in the other three representative Pseudomonas species, including P. aeruginosa, P. fluorescens and P. syringae. Our findings provide new insights into nitrate assimilation regulation by revealing the mechanism by which c-di-GMP inhibits nitrate assimilation via NasT.

The phosphodiesterase DibA interacts with the c-di-GMP receptor LapD and specifically regulates biofilm in Pseudomonas putida.

The ubiquitous bacterial second messenger c-di-GMP is synthesized by diguanylate cyclase and degraded by c-di-GMP-specific phosphodiesterase. The genome of Pseudomonas putida contains dozens of genes encoding diguanylate cyclase/phosphodiesterase, but the phenotypical-genotypical correlation and functional mechanism of these genes are largely unknown. Herein, we characterize the function and mechanism of a P. putida phosphodiesterase named DibA. DibA consists of a PAS domain, a GGDEF domain, and an EAL domain. The EAL domain is active and confers DibA phosphodiesterase activity. The GGDEF domain is inactive, but it promotes the phosphodiesterase activity of the EAL domain via binding GTP. Regarding phenotypic regulation, DibA modulates the cell surface adhesin LapA level in a c-di-GMP receptor LapD-dependent manner, thereby inhibiting biofilm formation. Moreover, DibA interacts and colocalizes with LapD in the cell membrane, and the interaction between DibA and LapD promotes the PDE activity of DibA. Besides, except for interacting with DibA and LapD itself, LapD is found to interact with 11 different potential diguanylate cyclases/phosphodiesterases in P. putida, including the conserved phosphodiesterase BifA. Overall, our findings demonstrate the functional mechanism by which DibA regulates biofilm formation and expand the understanding of the LapD-mediated c-di-GMP signaling network in P. putida.

Exploring the immune escape mechanisms in gastric cancer patients based on the deep AI algorithms and single-cell sequencing analysis.

Gastric cancer is a prevalent and deadly malignancy, and the response to immunotherapy varies among patients. This study aimed to develop a prognostic model for gastric cancer patients and investigate immune escape mechanisms using deep machine learning and single-cell sequencing analysis. Data from public databases were analysed, and a prediction model was constructed using 101 algorithms. The high-AIDPS group, characterized by increased AIDPS expression, exhibited worse survival, genomic variations and immune cell infiltration. These patients also showed immunotherapy tolerance. Treatment strategies targeting the high-AIDPS group identified three potential drugs. Additionally, distinct cluster groups and upregulated AIDPS-associated genes were observed in gastric adenocarcinoma cell lines. Inhibition of GHRL expression suppressed cancer cell activity, inhibited M2 polarization in macrophages and reduced invasiveness. Overall, AIDPS plays a critical role in gastric cancer prognosis, genomic variations, immune cell infiltration and immunotherapy response, and targeting GHRL expression holds promise for personalized treatment. These findings contribute to improved clinical management in gastric cancer.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Organo-organic interactions dominantly drive soil organic carbon accrual.

Organo-mineral interactions have been regarded as the primary mechanism for the stabilization of soil organic carbon (SOC) over decadal to millennial timescales, and the capacity for soil carbon (C) storage has commonly been assessed based on soil mineralogical attributes, particularly mineral surface availability. However, it remains contentious whether soil C sequestration is exclusively governed by mineral vacancies, making it challenging to accurately predict SOC dynamics. Here, through a 400-day incubation experiment using 13 C-labeled organic materials in two contrasting soils (i.e., Mollisol and Ultisol), we show that despite the unsaturation of mineral surfaces in both soils, the newly incorporated C predominantly adheres to "dirty" mineral surfaces coated with native organic matter (OM), demonstrating the crucial role of organo-organic interactions in exogenous C sequestration. Such interactions lead to multilayered C accumulation that is not constrained by mineral vacancies, a process distinct from direct organo-mineral contacts. The coverage of native OM by new C, representing the degree of organo-organic interactions, is noticeably larger in Ultisol (~14.2%) than in Mollisol (~5.8%), amounting to the net retention of exogenous C in Ultisol by 0.2-1.3 g kg-1 and in Mollisol by 0.1-1.0 g kg-1 . Additionally, organo-organic interactions are primarily mediated by polysaccharide-rich microbial necromass. Further evidence indicates that iron oxides can selectively preserve polysaccharide compounds, thereby promoting the organo-organic interactions. Overall, our findings provide direct empirical evidence for an overlooked but critically important pathway of C accumulation, challenging the prevailing "C saturation" concept that emphasizes the overriding role of mineral vacancies. It is estimated that, through organo-organic interactions, global Mollisols and Ultisols might sequester ~0.1-1.0 and ~0.3-1.7 Pg C per year, respectively, corresponding to the neutralization of ca. 0.5%-3.0% of soil C emissions or 5%-30% of fossil fuel combustion globally.

Protists regulate microbially mediated organic carbon turnover in soil aggregates.

Soil protists, the major predator of bacteria and fungi, shape the taxonomic and functional structure of soil microbiome via trophic regulation. However, how trophic interactions between protists and their prey influence microbially mediated soil organic carbon turnover remains largely unknown. Here, we investigated the protistan communities and microbial trophic interactions across different aggregates-size fractions in agricultural soil with long-term fertilization regimes. Our results showed that aggregate sizes significantly influenced the protistan community and microbial hierarchical interactions. Bacterivores were the predominant protistan functional group and were more abundant in macroaggregates and silt + clay than in microaggregates, while omnivores showed an opposite distribution pattern. Furthermore, partial least square path modeling revealed positive impacts of omnivores on the C-decomposition genes and soil organic matter (SOM) contents, while bacterivores displayed negative impacts. Microbial trophic interactions were intensive in macroaggregates and silt + clay but were restricted in microaggregates, as indicated by the intensity of protistan-bacterial associations and network complexity and connectivity. Cercozoan taxa were consistently identified as the keystone species in SOM degradation-related ecological clusters in macroaggregates and silt + clay, indicating the critical roles of protists in SOM degradation by regulating bacterial and fungal taxa. Chemical fertilization had a positive effect on soil C sequestration through suppressing SOM degradation-related ecological clusters in macroaggregate and silt + clay. Conversely, the associations between the trophic interactions and SOM contents were decoupled in microaggregates, suggesting limited microbial contributions to SOM turnovers. Our study demonstrates the importance of protists-driven trophic interactions on soil C cycling in agricultural ecosystems.

Trade-off between Pore-Throat Structure and Mineral Composition in Modulating the Stability of Soil Organic Carbon.

The preservation of soil organic carbon (OC) is an effective way to decelerate the emission of CO2 emission. However, the coregulation of pore structure and mineral composition in OC stabilization remains elusive. We employed the in situ nondestructive oxidation of OC by low-temperature ashing (LTA) combined with near edge X-ray absorption fine structure (NEXAFS), high-resolution microtomography (µ-CT), field emission electron probe microanalysis (FE-EPMA) with C-free embedding, and novel Cosine similarity measurement to investigate the C retention in different aggregate fractions of contrasting soils. Pore structure and minerals contributed equally (ca. 50%) to OC accumulation in macroaggregates, while chemical protection played a leading role in C retention with 53.4%-59.2% of residual C associated with minerals in microaggregates. Phyllosilicates were discovered to be more prominent than Fe (hydr)oxides in C stabilization. The proportion of phyllosilicates-associated C (52.0%-61.9%) was higher than that bound with Fe (hydr)oxides (45.6%-55.3%) in all aggregate fractions tested. This study disentangled quantitatively for the first time a trade-off between physical and chemical protection of OC varying with aggregate size and the different contributions of minerals to OC preservation. Incorporating pore structure and mineral composition into C modeling would optimize the C models and improve the soil C content prediction.

Ore improver additions alter livestock manure compost ecosystem C:N:P stoichiometry.

Deciphering the pivotal components of nutrient metabolism in compost is of paramount importance. To this end, ecoenzymatic stoichiometry, enzyme vector modeling, and statistical analysis were employed to explore the impact of exogenous ore improver on nutrient changes throughout the livestock composting process. The total phosphorus increased from 12.86 to 18.72 g kg-1, accompanied by a marked neutralized pH with ore improver, resulting in the Carbon-, nitrogen-, and phosphorus-related enzyme activities decreases. However, the potential C:P and N:P acquisition activities represented by ln(ßG + CB): ln(ALP) and ln(NAG): ln(ALP), were increased with ore improver addition. Based on the ecoenzymatic stoiometry theory, these changes reflect a decreasing trend in the relative P/N limitation, with pH and total phosphorus as the decisive factors. Our study showed that the practical employment of eco stoichiometry could benefit the manure composting process. Moreover, we should also consider the ecological effects from pH for the waste material utilization in sustainable agriculture.

Three new discovery effector proteins from Candidatus Liberibacter asiaticus psy62 inhibit plant defense through interaction with AtCAT3 and AtGAPA.

KEY MESSAGE: We identify three SDEs that inhibiting host defence from Candidatus Liberibacter asiaticus psy62, which is an important supplement to the pathogenesis of HLB. Candidatus Liberibacter asiaticus (CLas) is the main pathogen of citrus Huanglongbing (HLB). 38 new possible sec-dependent effectors (SDEs) of CLas psy62 were predicted by updated predictor SignalP 5.0, which 12 new SDEs were found using alkaline phosphate assay. Among them, SDE4310, SDE4435 and SDE4955 inhibited hypersensitivity reactions (HR) in Arabidopsis thaliana (Arabidopsis, At) and Nicotiana benthamiana leaves induced by pathogens, which lead to a decrease in cell death and reactive oxygen species (ROS) accumulation. And the expression levels of SDE4310, SDE4435, and SDE4955 genes elevated significantly in mild symptom citrus leaves. When SDE4310, SDE4435 and SDE4955 were overexpressed in Arabidopsis, HR pathway key genes pathogenesis-related 2 (PR2), PR5, nonexpressor of pathogenesis-related 1 (NPR1) and isochorismate synthase 1 (ICS1) expression significantly decreased and the growth of pathogen was greatly increased relative to control with Pst DC3000/AvrRps4 treatment. Our findings also indicated that SDE4310, SDE4435 and SDE4955 interacted with AtCAT3 (catalase 3) and AtGAPA (glyceraldehyde-3-phosphate dehydrogenase A). In conclusion, our results suggest that SDE4310, SDE4435 and SDE4955 are CLas psy62 effector proteins that may have redundant functions. They inhibit ROS burst and cell death by interacting with AtCAT3 and AtGAPA to negatively regulate host defense.

Exploring the Mechanism of H2S Synthesis in Male Bactrian Camel Poll Glands Based on Data Independent Acquisition Proteomics and Non-Targeted Metabolomics.

During estrus, the poll glands of male Bactrian Camels (Camelus Bactrianus) become slightly raised, exuding a large amount of pale yellow watery secretion with a characteristic odor that may contain hydrogen sulfide (H2S). However, whether H2S can be synthesized in the poll glands of male Bactrian Camels and its role in inducing camel estrus remains unclear. This study aimed to identify differentially expressed proteins (DEPs) and signaling pathways in the poll gland tissues of male Bactrian Camels using data independent acquisition (DIA) proteomics. Additionally, gas chromatography-mass spectrometry (GC-MS) was performed to identify differentially expressed metabolites (DEMs) in the neck hair containing secretions during estrus in male Bactrian Camels, to explore the specific expression patterns and mechanisms in the poll glands of camels during estrus. The results showed that cystathionine-γ-lyase (CTH) and cystathionine-ß-synthase (CBS), which are closely related to H2S synthesis in camel poll glands during estrus, were mainly enriched in glycine, serine, and threonine metabolism, amino acid biosynthesis, and metabolic pathways. In addition, both enzymes were widely distributed and highly expressed in the acinar cells of poll gland tissues in camels during estrus. Meanwhile, the neck hair secretion contains high levels of amino acids, especially glycine, serine, threonine, and cystathionine, which are precursors for H2S biosynthesis. These results demonstrate that the poll glands of male Bactrian Camels can synthesize and secrete H2S during estrus. This study provides a basis for exploring the function and mechanism of H2S in the estrus of Bactrian Camels.

Global, regional and national burden of Glaucoma: an update analysis from the Global Burden of Disease Study 2019.

PURPOSE: As the epidemiological and burden trends of glaucoma are changing, it is extremely necessary to re-investigate geographical differences and trends. Here we use data from the 2019 Global burden of Disease, which aims to report the prevalence and disability-adjusted life years of glaucoma injury to assess the latest epidemiological models and trends from 1990 to 2019. METHOD: Annual case numbers, age-standardized rates of prevalence, DALYs, and their estimated annual percentage changes (EAPCs) for glaucoma between 1990 and 2019 were derived from the GBD 2019 study. The relationship between glaucoma disease burden and social demographic index (SDI) was also investigated in this study. RESULTS: In 2019, there were 7.47 million prevalent cases and 0.75 million DALYs cases, which increased by 92.53% and 69.23% compared with 1990 respectively. The global age-standardized rate of prevalence (ASPR) and age-standardized rate of DALYs (ASDR) decreased during 1990-2019 (EAPC = - 0.55 and - 1, respectively). In 2019, the highest ASPR and ASDR of Glaucoma were all observed in Mali, whereas the lowest occurred in Taiwan (Province of China). In terms of gender, males were more likely to suffer from glaucoma than females, especially the elderly. CONCLUSIONS: The global prevalence and DALYs of glaucoma had an absolute increase during the past 30 years. The disease burden caused by glaucoma is closely related to socioeconomic level, age, gender, and other factors, and these findings provide a basis for policymakers from the perspective of social management.

KIAA1429 protects hepatocellular carcinoma cells from ferroptotic cell death with a m6 A-dependent posttranscriptional modification of SLC7A11.

N6 -methyladenosine (m6 A) modification represents the most abundant internal methylation of eukaryotic RNAs. KIAA1429 acts as a key component of the m6 A methyltransferase complex, but its function and mechanism in ferroptotic cell death of hepatocellular carcinoma (HCC) are barely defined. We found that KIAA1429 suppression triggered ferroptosis in HCC cells according to increased cell death, iron and MDA levels, C11-BODIPY-positive cells, ROS production and decreased GSH level. Ferroptosis inhibitors ferrostatin-1 (0.5 µM) and liproxstatin-1 (10 µM) blocked KIAA1429 suppression-induced ferroptosis of HCC cells. In addition, overexpressed KIAA1429 notably heightened the activity of cystine/glutamate antiporter (SLC7A11). SLC7A11 up-regulation partially hindered KIAA1429 inhibition-mediated ferroptosis of HCC cells. The regulation SLC7A11 by KIAA1429 was attenuated by global m6 A inhibitor cycloleucine (40 µM). RNA immunoprecipitation confirmed the binding of KIAA1429 to m6 A on SLC7A11 transcript. Additionally, it was proven that KIAA1429 inhibition mitigated HCC growth in subcutaneous xenograft mice through SLC7A11. Altogether, our findings first propose that KIAA1429 protects HCC cells from ferroptosis with a m6 A-dependent post-transcriptional modification of SLC7A11 and offer a novel insight into the dysregulated epi-transcriptomics in the context of HCC.

Humoral Immune Response and Safety of SARS-CoV-2 Vaccination in Pediatric Inflammatory Bowel Disease.

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5-17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 µg/mL (SD 67) and a median of 22 µg/mL (interquartile range 12-38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

The newest Oxford Nanopore R10.4.1 full-length 16S rRNA sequencing enables the accurate resolution of species-level microbial community profiling.

The long-read amplicon provides a species-level solution for the community. With the improvement of nanopore flowcells, the accuracy of Oxford Nanopore Technologies (ONT) R10.4.1 has been substantially enhanced, with an average of approximately 99%. To evaluate its effectiveness on amplicons, three types of microbiomes were analyzed by 16S ribosomal RNA (hereinafter referred to as "16S") amplicon sequencing using Novaseq, Pacbio sequel II, and Nanopore PromethION platforms (R9.4.1 and R10.4.1) in the current study. We showed the error rate, recall, precision, and bias index in the mock sample. The error rate of ONT R10.4.1 was greatly reduced, with a better recall in the case of the synthetic community. Meanwhile, in different types of environmental samples, ONT R10.4.1 analysis resulted in a composition similar to Pacbio data. We found that classification tools and databases influence ONT data. Based on these results, we conclude that the ONT R10.4.1 16S amplicon can also be used for application in environmental samples. IMPORTANCE The long-read amplicon supplies the community with a species-level solution. Due to the high error rate of nanopore sequencing early on, it has not been frequently used in 16S studies. Oxford Nanopore Technologies (ONT) introduced the R10.4.1 flowcell with Q20+ reagent to achieve more than 99% accuracy as sequencing technology advanced. However, there has been no published study on the performance of commercial PromethION sequencers with R10.4.1 flowcells on 16S sequencing or on the impact of accuracy improvement on taxonomy (R9.4.1 to R10.4.1) using 16S ONT data. In this study, three types of microbiomes were investigated by 16S ribosomal RNA (rRNA) amplicon sequencing using Novaseq, Pacbio sequel II, and Nanopore PromethION platforms (R9.4.1 and R10.4.1). In the mock sample, we displayed the error rate, recall, precision, and bias index. We observed that the error rate in ONT R10.4.1 is significantly lower, especially when deletions are involved. First and foremost, R10.4.1 and Pacific Bioscience platforms reveal a similar microbiome in environmental samples. This study shows that the R10.4.1 full-length 16S rRNA sequences allow for species identification of environmental microbiota.

Microbial autotrophy explains large-scale soil CO2 fixation.

Microbial communities play critical roles in fixing carbon from the atmosphere and fixing it in the soils. However, the large-scale variations and drivers of these microbial communities remain poorly understood. Here, we conducted a large-scale survey across China and found that soil autotrophic organisms are critical for explaining CO2 fluxes from the atmosphere to soils. In particular, we showed that large-scale variations in CO2 fixation rates are highly correlated to those in autotrophic bacteria and phototrophic protists. Paddy soils, supporting a larger proportion of obligate bacterial and protist autotrophs, display four-fold of CO2 fixation rates over upland and forest soils. Precipitation and pH, together with key ecological clusters of autotrophic microbes, also played important roles in controlling CO2 fixation. Our work provides a novel quantification on the contribution of terrestrial autotrophic microbes to soil CO2 fixation processes at a large scale, with implications for global carbon regulation under climate change.

Functional Two-Way Crosstalk Between Brain and Lung: The Brain-Lung Axis.

The brain has many connections with various organs. Recent advances have demonstrated the existence of a bidirectional central nervous system (CNS) and intestinal tract, that is, the brain-gut axis. Although studies have suggested that the brain and lung can communicate with each other through many pathways, whether there is a brain-lung axis remains still unknown. Based on previous findings, we put forward a hypothesis: there is a cross-talk between the central nervous system and the lung via neuroanatomical pathway, endocrine pathway, immune pathway, metabolites and microorganism pathway, gas pathway, that is, the brain-lung axis. Beyond the regulation of the physiological state in the body, bi-directional communication between the lung and the brain is associated with a variety of disease states, including lung diseases and CNS diseases. Exploring the brain-lung axis not only helps us to understand the development of the disease from different aspects, but also provides an important target for treatment strategies.

Synthesis and biological evaluation of N-(benzene sulfonyl)acetamide derivatives as anti-inflammatory and analgesic agents with COX-2/5-LOX/TRPV1 multifunctional inhibitory activity.

In this study, a series of structurally novel N-(benzene sulfonyl) acetamide derivatives were designed, synthesized, and biologically evaluated as COX-2/5-LOX/TRPV1 multitarget inhibitors for anti-inflammatory and analgesic therapy. Among them, 9a and 9b displayed favorable COX-2 (9a IC50 = 0.011 µM, 9b IC50 = 0.023 µM), 5-LOX (9a IC50 = 0.046 µM, 9b IC50 = 0.31 µM) and TRPV1 (9a IC50 = 0.008 µM, 9b IC50 = 0.14 µM) inhibitory activities. The pharmacokinetic (PK) study of 9a in SD rats at the dosage of 10 mg/kg demonstrated a high oral exposure, an acceptable clearance and a favorable bioavailability (Cmax = 5807.18 ± 2657.83 ng/mL, CL = 3.24 ± 1.47 mL/min/kg, F = 96.8 %). Further in vivo efficacy studies illustrated that 9a was capable of ameliorating formalin-induced pain and inhibiting capsaicin-induced ear edema.

Core Species Derived from Multispecies Interactions Facilitate the Immobilization of Cadmium.

Microbial consortia have opened new avenues for heavy-metal remediation. However, the limited understanding of the overall effect of interspecific interactions on remediation efficacy hinders its application. Here, the effects of multispecies growth and biofilm formation on Cd immobilization were explored from direct and multiple interactions through random combinations of two or three rhizosphere bacteria. In monocultures, Cd stress resulted in an average decrease in planktonic biomass of 26%, but through cooperation, the decrease was attenuated in dual (21%) and triple cultures (13%), possibly involving an increase in surface polysaccharides. More than 65% of the co-cultures exhibited induction of biofilm formation under Cd stress, which further enhanced the role of biofilms in Cd immobilization. Notably, excellent biofilm-forming ability or extensive social induction makes Pseudomonas putida and Brevundimonas diminuta stand out in multispecies biofilm formation and Cd immobilization. These two core species significantly increase the colonization of soil microorganisms on rice roots compared to the control, resulting in a 40% decrease in Cd uptake by rice. Our study enhances the understanding of bacterial interactions under Cd stress and provides a novel strategy for adjusting beneficial soil consortia for heavy-metal remediation.

Dichotomous Role of Humic Substances in Modulating Transformation of Antibiotic Resistance Genes in Mineral Systems.

Widespread antibiotic resistance genes (ARGs) have emerged as a focus of attention for public health. Transformation is essential for ARGs dissemination in soils and associated environments; however, the mechanisms of how soil components contribute to the transformation of ARGs remain elusive. Here we demonstrate that three representative mineral-humic acid (HA) composites exert contrasting influence on the transformation of plasmid-borne ARGs in Bacillus subtilis. Mineral surface-bound HA facilitated transformation in kaolinite and montmorillonite systems, while an inhibitory effect of HA was observed for goethite. The elevated transformation by HA-coated kaolinite was mainly attributed to the enhanced activity of competence-stimulating factor (CSF), while increased transformation by montmorillonite-HA composites was assigned to the weakened adsorption affinity of DNA and enhanced gene expression induced by flagella-driven cell motility. In goethite system, HA played an overriding role in suppressing transformation via alleviation of cell membrane damage. The results obtained offer insights into the divergent mechanisms of humic substances in modulating bacterial transformation by soil minerals. Our findings would help for a better understanding on the fate of ARGs in soil systems and provide potentials for the utilization of soil components, particularly organic matter, to mitigate the spread of ARGs in a range of settings.